Wang Yingrui, Krämer Stephanie, Loof Tanja, Martini Sebastian, Kron Susanne, Kawachi Hiroshi, Shimizu Fuijo, Neumayer Hans-H, Peters Harm
Department of Nephrology and Center of Cardiovascular Research, Charité University Medicine Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany.
Kidney Int. 2005 Jul;68(1):47-61. doi: 10.1111/j.1523-1755.2005.00380.x.
A critical role of soluble guanylate cyclase and nitric oxide-dependent cyclic 3',5'-guanosine monophosphate (cGMP) production for glomerular matrix expansion has recently been documented in a rat model of acute anti-thy1 glomerulonephritis. The present study analyzes the renal activity of the nitric oxide-cGMP signaling cascade in and the effect of the specific soluble guanylate cyclase stimulator Bay 41-2272 on a progressive model of anti-thy1-induced chronic glomerulosclerosis.
Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized rats. One week after disease induction, animals were randomly assigned to chronic glomerulosclerosis, chronic glomerulosclerosis plus Bay 41-2272 (10 mg/kg body weight/day) or chronic glomerulosclerosis plus hydralazine (15 mg/kg body weight/day). In week 16, analysis included effects on systolic blood pressure, proteinuria, kidney function, glomerular and tubulointerstitial matrix protein accumulation, expression of transforming growth factor-beta1 (TGF-beta1), fibronectin and plasminogen activator inhibitor type 1 (PAI-1), macrophage infiltration, cell proliferation, basal and nitric oxide-stimulated cGMP production as well as tubulointerstitial mRNA expression of alpha 1 and beta 1 soluble guanylate cyclase.
The moderately elevated systolic blood pressure seen in the chronic glomerulosclerosis group was comparably decreased by both treatments. Compared to normal controls, soluble guanylate cyclase mRNA expression and nitric oxide-stimulated cGMP production were up-regulated in the tubulointerstitium of the untreated chronic glomerulosclerosis animals, while its activity was decreased in glomeruli. Bay 41-2272 treatment enhanced glomerular and tubulointerstitial nitric oxide-cGMP signaling significantly. This went along with markedly reduced glomerular and tubulointerstitial macrophage infiltration, number of proliferating cells, matrix expression and accumulation, as well as improved kidney function. In contrast, hydralazine therapy did not significantly affect renal nitric oxide-cGMP signaling, macrophage number, cell proliferation, matrix protein expression and accumulation.
Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.
最近在急性抗 Thy1 肾小球肾炎大鼠模型中已证明可溶性鸟苷酸环化酶及一氧化氮依赖性环 3',5'-鸟苷单磷酸（cGMP）生成在肾小球基质扩张中起关键作用。本研究分析了一氧化氮 - cGMP 信号级联在抗 Thy1 诱导的慢性肾小球硬化进展模型中的肾脏活性，以及特异性可溶性鸟苷酸环化酶刺激剂 Bay 41 - 2272 的作用。
通过向单侧肾切除的大鼠注射抗 Thy1 抗体诱导抗 Thy1 肾小球硬化。疾病诱导 1 周后，将动物随机分为慢性肾小球硬化组、慢性肾小球硬化加 Bay 41 - 2272（10 毫克/千克体重/天）组或慢性肾小球硬化加肼屈嗪（15 毫克/千克体重/天）组。在第 16 周，分析内容包括对收缩压、蛋白尿、肾功能、肾小球和肾小管间质基质蛋白积累、转化生长因子 -β1（TGF -β1）、纤连蛋白和纤溶酶原激活物抑制剂 1 型（PAI -1）表达、巨噬细胞浸润、细胞增殖、基础及一氧化氮刺激的 cGMP 生成的影响，以及α1 和β1 可溶性鸟苷酸环化酶的肾小管间质 mRNA 表达。
两种治疗方法均使慢性肾小球硬化组中适度升高的收缩压得到类似程度的降低。与正常对照组相比，未治疗的慢性肾小球硬化动物的肾小管间质中可溶性鸟苷酸环化酶 mRNA 表达及一氧化氮刺激的 cGMP 生成上调，而肾小球中的活性降低。Bay 41 - 2272 治疗显著增强了肾小球和肾小管间质的一氧化氮 - cGMP 信号传导。这伴随着肾小球和肾小管间质巨噬细胞浸润、增殖细胞数量、基质表达和积累明显减少，以及肾功能改善。相比之下，肼屈嗪治疗对肾脏一氧化氮 - cGMP 信号传导、巨噬细胞数量、细胞增殖、基质蛋白表达和积累没有显著影响。
在抗 Thy1 诱导的慢性肾小球硬化中，肾小球和肾小管间质可溶性鸟苷酸环化酶活性发生不一致的改变。Bay 41 - 2272 刺激可溶性鸟苷酸环化酶信号传导至少部分以血压非依赖性方式限制了该模型向肾小管间质纤维化和肾功能损害的进展过程。结果表明可溶性鸟苷酸环化酶激活可对抗慢性肾病中的纤维化和疾病进展。
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